tbuckley/cabot-search huggingface dataset:
Abstract 3798: lncRNA LIMp27 promotes p53-defective cancer pathogenesis
Authors: Ting La, Song Chen, Xiao Hong Zhao, Yuan Yuan Zhang, Yu Chen Feng, Xu Dong Zhang, Lei Jin
Journal: Cancer Research (2023)

Abstract Inactivation of p53 occurs in approximately 50% of human cancers, where p53-mediated p21 activation is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, we show that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and promotes proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA, leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover a lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers. Citation Format: Ting La, Song Chen, Xiao Hong Zhao, Yuan Yuan Zhang, Yu Chen Feng, Xu Dong Zhang, Lei Jin. lncRNA LIMp27 promotes p53-defective cancer pathogenesis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3798.
Abstract 5352: Targeting DNA methylation in T cells to improve the efficacy of immunotherapy
Authors: Pengtao Dang, Xiao Wang, Haiqi Zhu, Jia Wang, Tingbo Guo, Xinyu Zhou, Paveethran Swaminathan, Chi Zhang, Sha Cao
Journal: Cancer Research (2023)

Abstract T-cells are critical mediators of immunity and immunologic memory. Their cell fates are regulated in part through epigenetic mechanisms, including DNA methylation. Recent genome-wide methylation analyses have revealed dynamic alterations in the methylome at various stages of development and differentiation of T cells. At single cell level, it is not easy to simultaneously collect RNA-seq and RBBS methylation profiling. An important task is to understand the expression change of which genes and pathways are regulated by DNA methylations, especially for the ones that are associated with functional variations in the T cells from tumor microenvironment.In this study, we developed a computational approach based on our recently developed metabolic flux estimation to estimate cell-wise global DNA methylation activity level by using scRNA-seq data. We also hypothesize that the global DNA methylation activity level in one cell determines most of the DNA methylation level in gene-specific DNA methylations. Hence, the dependency between gene-specific DNA methylation and expression could be imputed by the dependency between predicted global DNA methylation input level and the gene expression. We validated our method to impute cell-wise global DNA methylation level by using four independent sets of paired gene expression and DNA methylation data. Noted, our prediction of global DNA methylation activity is from a pure metabolic perspective. We found that two metabolic reaction rates, named metabolic flux from methionine to SAM and SAM to SAH, purely predicted by using gene expression data can accurately impute DNA methylation activity in all validating data sets. Our method enables further identification of the disease/cell context specific contributor of DNA methylation, i.e., the genes high contribution to DNA methylations in each individual cell or cell groups. We applied our method on scRNA-seq data of different T cell types extracted from TME of lung, liver, and colon cancer. We have seen that exhausted T cells, especially the ones with decreased Granzymes and PRF1 are associated with increased global DNA methylation level and related genes, suggesting the potential clinical implications in targeting DNA methylation to improve the efficacy of immunotherapies. Citation Format: Pengtao Dang, Xiao Wang, Haiqi Zhu, Jia Wang, Tingbo Guo, Xinyu Zhou, Paveethran Swaminathan, Chi Zhang, Sha Cao. Targeting DNA methylation in T cells to improve the efficacy of immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5352.
Abstract 6344: Recombinant Immunotoxin exhibited targeted killing of Trop2 overexpressing tumour cells lines
Authors: Dennis Makafui Dogbey, Sizalobuhle Masuku, Stefan Barth
Journal: Cancer Research (2023)

Abstract Introduction: The high prevalence of cervical cancer remains a global challenge particularly in developing countries where its therapy is principally by chemoradiation marked by severe toxicities. Antibody-based therapy targeting specific overexpressed surface antigen has proven as a promising strategy. Tumor-associated calcium signal transducer 2 (Trop2), also known as epithelial glycoprotein-1 antigen, is a membrane protein found in epithelial tissues involved in cellular signalling, migration, proliferation, and differentiation in normal cells. Its overexpression is validated in several tumor types including basal, squamous and adenocarcinomas of the cervix, breast, colon, and gastrointestinal tracts. Due to its differential overexpression, Trop2 is a viable therapeutic marker whereby a recombinant immunotoxin composed of a single chain variable antibody fragment (scFv) armed with Pseudomonas exotoxin A (Anti-Trop2-ETA) may be delivered for targeted killing of such tumors. Methods: Plasmids encoding Anti-Trop2-ETA were designed in silico by fusion of anti-Trop2 single chain variable fragment (scFv) antibody to the N-terminus of Pseudomonas exotoxin A and then cloned into an pMT backbone. Expression was performed in BL21 E. Coli cells under osmotic stress and then Anti-Trop2-ETA was purified by IMAC via an N-terminus encoded polyhistidine tag. Purified fractions were structurally characterized by SDS PAGE gel and immunoblotting to confirm the presence of the Anti-Trop2-ETA protein to be used for treatment of tumor cell lines. Trop2 expression cervical cancer and breast tumor cell lines were confirmed, and cells were treated with Anti-Trop2-ETA. Results: Dose dependent killing by Anti-Trop2-ETA was observed in the Trop2 expressing tumor cell lines. IC50 values were significantly lower for Trop2 expressing cells as compared to control cells lacking Trop2 expression. Conclusion: Here, we demonstrated antigen specific killing of Trop2 overexpressing tumor cells in vitro. Targeted deployment of recombinant immunotoxin to specifically engage and kill Trop2 positive cells is a potential approach for cancer therapeutics. As such, the ability of the rIT to specifically target and kill Trop2 expressing tumors is an important initial finding towards the possibility of antigen-dependent elimination of Trop2 expressing cancer cells. Ongoing evaluations are aimed at antigen dependent biological activity as well as pharmacokinetics of the rIT in tumor bearing in vivo models. Citation Format: Dennis Makafui Dogbey, Sizalobuhle Masuku, Stefan Barth. Recombinant Immunotoxin exhibited targeted killing of Trop2 overexpressing tumour cells lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6344.
Abstract 1590: Identification and characterization of a first-generation inhibitor of claudin-1 to inhibit colon cancer progression and metastasis
Authors: Iram Fatima, Jaya Prakash Uppada, Yashpal S. Chhonker, Saiprasad Gowrikumar, Susmita Barman, Sourav Roy, Kirsten T. Tolentino, Nicholas Palermo, Amar Natarajan, Daniel R. Beauchamp, Alex Vecchio, Daryl J. Murry, Amar B. Singh, Corey R. Hopkins, Punita Dhawan
Journal: Cancer Research (2023)

Abstract Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Thus, developing novel and targeted therapies for inhibiting CRC progression and metastasis is urgent. Several studies, including ours, have reported a causal role for an upregulated claudin-1 expression in promoting CRC metastasis through the activation of the Src and β-catenin-signaling. In murine models of colon tumorigenesis, claudin-1 overexpression promotes oncogenic properties such as transformation and invasiveness. Conversely, the downregulation of claudin-1 inhibits colon tumorigenesis. Despite being a desirable target for cancer treatment, there are currently no known claudin-1 inhibitors with antitumor efficacy. Using a rigorous analytical design and implementing in-vitro and in-vivo testing and a brief medicinal chemistry campaign, we identified a claudin-1-specific inhibitor and named it I-6. Despite its high potency, I-6 was rapidly cleared in human liver microsomes. We, therefore, synthesized I-6 analogs and discovered a novel small molecule, PDS-0330. We determined that PDS0330 inhibits claudin-1-dependent CRC progression without exhibiting toxicity in in-vitro and in-vivo models of CRC and that it binds directly and specifically to claudin-1 with micromolar affinity. Further analyses revealed that PDS-0330 exhibits antitumor and chemosensitizer activities with favorable pharmacokinetic properties by inhibiting the association with metastatic oncogene Src. Overall, our data propose that PDS-0330 interferes with claudin-1/Src association to inhibit CRC progression and metastasis. Our findings are of direct clinical relevance and may open new therapeutic opportunities in colon cancer treatment and/or management by targeting claudin-1. Citation Format: Iram Fatima, Jaya Prakash Uppada, Yashpal S. Chhonker, Saiprasad Gowrikumar, Susmita Barman, Sourav Roy, Kirsten T. Tolentino, Nicholas Palermo, Amar Natarajan, Daniel R. Beauchamp, Alex Vecchio, Daryl J. Murry, Amar B. Singh, Corey R. Hopkins, Punita Dhawan. Identification and characterization of a first-generation inhibitor of claudin-1 to inhibit colon cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1590.
Abstract 2090: Comprehensive interrogation of gene lists from genome-scale cancer screens with oncoEnrichR
Authors: Sigve Nakken, Sveinung Gundersen, Fabian L. Bernal, Dimitris Polychronopoulos, Eivind Hovig, Jørgen Wesche
Journal: Cancer Research (2023)

Abstract Genome-scale screening experiments in cancer produce long lists of candidate genes that require extensive interpretation for biological insight and prioritization for follow-up studies. Interrogation of gene lists frequently represents a significant and time-consuming undertaking, in which experimental biologists typically combine results from a variety of bioinformatics resources in an attempt to portray and understand cancer relevance. As a means to simplify and strengthen the support for this endeavor, we have developed oncoEnrichR, a flexible bioinformatics tool that allows cancer researchers to comprehensively interrogate a given gene list along multiple facets of cancer relevance. oncoEnrichR differs from general gene set analysis frameworks through the integration of an extensive set of prior knowledge specifically relevant for cancer, including ranked gene-tumor type associations, literature-supported proto-oncogene and tumor suppressor gene annotations, target druggability data, regulatory interactions, synthetic lethality predictions, as well as prognostic associations, gene aberrations, and co-expression patterns across tumor types. The software produces a structured and user-friendly analysis report as its main output, where versions of all underlying data resources are explicitly logged, the latter being a critical component for reproducible science. We demonstrate the usefulness of oncoEnrichR through interrogation of two candidate lists from proteomic and CRISPR screens. oncoEnrichR is freely available as a web-based workflow hosted by the Galaxy platform (https://oncotools.elixir.no), and can also be accessed as a stand-alone R package (https://github.com/sigven/oncoEnrichR). Citation Format: Sigve Nakken, Sveinung Gundersen, Fabian L. Bernal, Dimitris Polychronopoulos, Eivind Hovig, Jørgen Wesche. Comprehensive interrogation of gene lists from genome-scale cancer screens with oncoEnrichR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2090.
Abstract 221: Development of a rapid, highly sensitive cell-free RNA NGS assay for the detection of gene fusion and splicing variants in cancers
Authors: fang liu, xiangying sun, jianrong dong, kemin zhou, yong huang, shidong jia, pan du, Binggang xiang, shujun luo
Journal: Cancer Research (2023)

Abstract Background: Utility of cell-free nucleic acids (cf-NAs) for early detection and surveillance of tumor represents a new path in personalized medicine. Gene fusions, which usually arise from chromosomal rearrangement, play pivotal roles in numerous human malignancies and have been exploited for disease diagnosis and therapeutics. RNA sequencing, which is not influenced by the complication of introns, is considered superior to DNA sequencing for the identification of fusion genes and splicing variants, and has emerged as a critical tool in cancer liquid biopsy. Methods: We developed a novel approach of preparing strand-specific RNA-Seq libraries. The cDNA produced from the cell-free RNA (cfRNA) samples were labelled with unique molecular identifiers (UMI) during library construction. The libraries were enriched using hybrid capture and the sequencing data were analyzed using Predicine in-house analysis pipeline. To assess the performance of the newly developed cfRNA assay, we compared it with a variety of commercial RNA library kits. Results: The new RNA library construction workflow was streamlined, and it reduces the library preparation time from 2 days to 6 hours with less than 1 h of hands-on time. The yield of the library prepared by the new method was higher than those of the commonly used commercial kits on the market. Sequencing analysis and Droplet Digital PCR (ddPCR) measurement both revealed that our assay was more sensitive in detecting gene fusions and splicing variants in cfRNA than other commercial kits. The assay can reliably detect fusion/splicing variants down to the level of &amp;lt;10 copies of input cfRNA with high specificity. Conclusions: We developed a new RNA library preparation method that produced strand-specific libraries from low input quantities of cfRNA in a fast, simple, and robust manner. This RNA-Seq assay has demonstrated superior performance in known fusion detection and novel fusion discovery in cfRNA. Citation Format: fang liu, xiangying sun, jianrong dong, kemin zhou, yong huang, shidong jia, pan du, Binggang xiang, shujun luo. Development of a rapid, highly sensitive cell-free RNA NGS assay for the detection of gene fusion and splicing variants in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 221.
Abstract 3263: Implications for cancer viroimmunotherapy: a new adenovirus capsid sensor
Authors: Andrew Gregg Gillard, Dong Ho Shin, Virginia Laspidea, Hong Jiang, Fan Xuejun, Yanhua Yi, Marta M. Alonso, Juan Fueyo, Candelaria Gomez-Manzano
Journal: Cancer Research (2023)

Abstract The median survival for glioblastoma (GBM) patients is 12-15 months, with a five-year survival rate of less than 10% despite aggressive treatment with surgery, radiotherapy, and chemotherapy. Oncolytic virotherapy is emerging as a promising approach to reprogramming the immunosuppressed microenvironment of GBMs and restoring anti-tumor immunity. Delta-24-RGD is an oncolytic adenovirus that has shown favorable results in phase I clinical trials (NCT00805376; NCT03178032). However, immune responses functionally cleared the virus within weeks of administration, limiting anti-cancer efficacy to a subset (~20%) of patients. A better understanding of the innate immune response against adenoviruses may provide the rationale for developing improved anticancer approaches. Using bulk RNA sequencing, we have examined the transcriptome of normal lung fibroblasts infected with wild-type adenovirus. Ingenuity pathway analysis (IPA) showed upregulation of several immune response-related pathways, including interferon response factor 3 (IRF3). Interestingly, these analyses also showed an unexpected upregulation of the Non-POU Domain Containing Octamer Binding (NONO) pathway during adenoviral infection. In fact, upstream regulators analyses showed a 7-fold increase in the NONO pathway in two different cell lines. Increases in NONO expression changes in response to adenovirus treatment were validated by western blot. Furthermore, co-immunoprecipitation assays showed that NONO binds to adenoviral capsid proteins during infection and to the foreign DNA sensor cyclic GMP AMP synthase (cGAS), which is critical for the activation of the innate immunity, via IRF3. In our proposed model, NONO protein binds to the adenoviral capsid protein and associates with the sensor cGAS in the nucleus to enable sensing of viral nucleic acid. In conclusion, we uncovered a new mechanism for detecting adenovirus infection that involves the interaction of adenoviral capsid proteins with members of the NONO pathway in the nucleus of the infected cell. Further studies are in progress to examine to which extent adenoviruses unable to bind NONO may persist longer in the infected tumors than unmodified adenoviruses and whether the persistence of the virus in the tumor correlates with enhanced anti-glioma effect. Citation Format: Andrew Gregg Gillard, Dong Ho Shin, Virginia Laspidea, Hong Jiang, Fan Xuejun, Yanhua Yi, Marta M. Alonso, Juan Fueyo, Candelaria Gomez-Manzano. Implications for cancer viroimmunotherapy: a new adenovirus capsid sensor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3263.
Abstract 2028: Using bioinformatic analysis of proteomic data to probe novel drug mechanism of action
Authors: Weining Chen, Nicholas Woods, Fangfang Qiao, Henry Chun Hin Law, Sankarasubramanian Jagadesan, Chittibabu Guda, Raymond C. Bergan
Journal: Cancer Research (2023)

Abstract Introduction: Metastasis is a major cause of death for patients with solid tumors. Our group has discovered a selective inhibitor of cell motility, KBU2046, that blocks the activation of Raf1 by inhibiting the phosphorylation of ser338 on its activation motif (Nature Communications 2018). To better understand the effect of KBU2046 on human prostate cancer (PCa) cells, we undertook a proteomic analysis. Experimental Procedures: After treatment of PC3 cells with KBU2046 or vehicle (N=3/group), protein expression of whole cell lysate was quantified by Liquid Chromatography/Tandem Mass Spectrometry analysis (LC-MS/MS). In separate experiments (N=4), membrane fractions were isolated, and LC-MS/MS was performed after Tandem Mass Tag (TMT) labeling. Resultant data were analyzed by several complementary bioinformatics tools, including: Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) term analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Ingenuity Pathway Analysis (IPA), and protein-protein interaction (PPI) network analysis to characterize the proteins that were significantly differentially expressed upon KBU2046 treatment. Results: Independent bioinformatic analyses of differentially expressed proteins affected by KBU2046 treatment identify significantly enriched processes related to cell motility, inclusive of effects on structural machinery. This constitutes orthogonal confirmation of KBU2046’s known effects on cell motility. Of importance, major effects on cellular energy-generating processes were also identified. This is consistent with prior studies that found changes in motility induce obligatorye changes in cellular energy requirements. Our focused analysis of membrane fractions identified changes in membranous compartments, providing a relevant positive control for bioinformatic analysis, which we confirmed by Western blot. Analytics also pointed to a major role for adhesion proteins in response to KBU2046, consistent with our prior identification of primary effects on cell migration. Conclusions: These findings provide orthogonal mechanistically relevant support for a novel acting agent. They highlight the ability of proteomics and bioinformatic tools to efficiently probe the mechanism of action and global impact on PCa in response to treatment. Citation Format: Weining Chen, Nicholas Woods, Fangfang Qiao, Henry Chun Hin Law, Sankarasubramanian Jagadesan, Chittibabu Guda, Raymond C. Bergan. Using bioinformatic analysis of proteomic data to probe novel drug mechanism of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2028.
Abstract 6288: Discovery and characterization of potent, selective CBP degraders
Authors: Laura La Bonte, Darshan Sappal
Journal: Cancer Research (2023)

Abstract CREB binding protein (CBP) and E1A binding protein (p300) are paralog histone acetyltransferases involved in many cellular processes via their activity as transcription factor co-activators. Dysregulation of one or both proteins has been implicated in a variety of cancers. Due to the high homology between CBP and p300, identification of selective chemical matter that specifically and directly targets CBP has proven challenging. Here, we describe a potent, highly selective CBP heterobifunctional degrader with selective biological activity in CBP dependent cancer lines. Citation Format: Laura La Bonte, Darshan Sappal. Discovery and characterization of potent, selective CBP degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6288.